In tissue culture, cardiomyocyte hypertrophy occurs in response to mechanical stretching or exposure to Gq activating cardiotrophic factors. In vivo cardiac hypertrophy in hemodynamically overloaded hearts is also mediated in part by autocrine or paracrine activation of Gq coupled receptors. However, the reasons for decompensation and failure of cardiac hypertrophy which is initially "compensatory" are not known. Recently it was observed that Gq signaling at levels exceeding those which stimulate cardiomyocyte hypertrophy causes apoptotic cardiomyocyte death, suggesting a plausible mechanism for hypertrophy decompensation. We have created transgenic mice overexpressing the alpha subunit of Gq (Galphaq) and observed autonomous activation of protein kinase C (PKC) and development of nonfailing cardiac hypertrophy recapitulating molecular, cellular and functional features of pressure overloaded hearts. When Gq signaling and PKC activity were further enhanced, transition to a dilated cardiomyopathy occurred with widespread cardiomyocyte apoptosis. Thus, Galphaq overexpressors represent a unique model of cardiac hypertrophy resulting purely from autonomous activation of intrinsic signaling pathways, in which manipulation of these signaling events causes apparent apoptotic heart failure. We will utilize this transgenic model to: (SA numberl) Determine the effects of Gq-coupled receptor agonists verses peptide growth factors on cardiomyocyte hypertrophy or apoptosis, and on cardiac anatomy and function; (SA number2) Identify critical downstream mediators of cardiomyocyte apoptosis in agonist-stimulated Galphaq overexpressors by assaying the expression and activities of candidate kinases and apoptosis signaling proteins; (SA number3) Determine the apoptotic effects of cardiomyocyte PKC alpha, delta and epsilon signaling in comparison with signaling through Bax by combined transgenesis of Gaphaq with dominant negative PKCs or the apoptotic inhibitor Bcl-x1; (SA number4) Rescue Galphaq-mediated hypertrophy decompensation and cardiomyocyte apoptosis by restoring adenylyl cyclase activity through combined transgenesis with adenylyl cyclase type 5.